Novel approaches for treatment of autoimmune diseases are emerging, as we better understand the molecular mechanisms of autoimmunity. A shift from nonspecific treatment with associated toxicity to specific, targeted molecular therapies is sorely needed. Our therapeutic approach focuses on targeting the IgG protection receptor FcRn, which plays a very restricted role in immune system. We believe that the blockade of FcRn-mediated protection will have a substantial effect on antibody responses, IgG homeostasis, and the modulation of autoimmune diseases with autoantibody etiology. To facilitate the extrapolation to humans, we will use humanized mouse models for therapeutic evaluation. Our experimental design is to first test potential therapeutic approaches for their ability to inhibit the binding of IgG to the human (hu) huFcRn in vitro. We will then test them in vivo in mice that lack mouse FcRn but transgenically co-express huFcRn and hu[unreadable]2m. Our long-term goal is to determine whether we can use the same therapeutic approaches to ameliorate arthritis and systemic lupus erythematosus.